Restenosis after angioplasty procedures or intracoronary stenting is a significant clinical problem. A dominant cellular event in the re-narrowing of the vascular lumen after angioplasty is smooth muscle cell (SMC) proliferation and migration. After vascular injury, the SMCs start to proliferate and then migrate into the developing neointima, thus becoming the major cellular substrate of the restenotic tissue. The rough-surfaced endoplasmic reticulum in SMCs can express a large number of growth-regulatory molecules and extracellular matrix (ECM) components.
SMC migration is regulated by insulin-like growth factor-1 (ILGF-1), platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), as well as several other signaling factors. However, the precise molecular mechanisms that regulate SMC migration are not fully understood.
Numerous drugs have been tested for their ability to prevent restenosis. However, most have failed to reduce the incidence of restenosis appreciably. The control of SMC proliferation by activation of tumor suppressor genes such as p53, PTEN (phosphatase and tensin homolog mutated in multiple advanced cancers), and blocking the genes involved in cell-cycle progression was a recent development with potentially relevant clinical applications. For example, PTEN has been reported to regulate cardiac myocyte hypertrophy and survival as well as many of the angiogenic responses of vascular endothelial cells. A recent report also show that overexpression of PTEN could inhibit growth factor-induced proliferation, migration, and survival of vascular smooth muscle cells. The inhibitory effect of PTEN on neointimal formation was demonstrated in a rat carotid arterial balloon injury model and in aorteriocoronary saphenous vein grafts. However, the role of PTEN in molecular-signaling mechanisms, such as cell-cycle modulation, has not yet been elucidated.
It would be useful to have effective methods of treating and/or preventing the factors that cause restenosis, arteriosclerosis, and/or neointimal hyperplasia.